The purpose of this Program Project Grant is to identify brain circuitry that regulates EEG arousal and airway opening during obstructive sleep apnea (OSA), and to design and test new therapies in OSA patients based on that information. Patients with OSA lose tone in their airway dilator muscles as they sleep, resulting in collapse of the airway and apnea. As CO2 levels rise, there are progressively more vigorous attempts to breathe, until finally there is EEG arousal, the airway opens, and breathing is re-established. These arousals occur as many as several hundred times per night, fragmenting sleep and resulting in cognitive impairments; accelerated atherosclerosis, and increased risk of stroke and myocardial infarction; and metabolic syndrome with obesity, which in turn makes the OSA worse and further increases cardiovascular risk. Our investigators have found that in some apnea cycles, patients may generate sufficient airway dilator tone to reopen the airway, without EEG arousal. In such subjects, delaying the EEG arousal may permit the patients to generate enough airway dilator tone to avoid arousals. Our goals then are to find pharmacological means to delay EEG arousal while augmenting airway dilator tone, so that OSA patients have fewer apneas, or if they occur, are able to re-establish the airway without EEG arousal. Projects 1-3 work on the first goal by identifying the brain circuitry that causes the arousal to rising arterial CO2. These projects seek to identify the neurotransmitters and receptors involved in CO2 arousal, as targets for pharmacological manipulation. Project 4 focuses on the control of the genioglossus muscle, the largest airway dilator. It will examine the inputs to the genioglossus motor neurons that suppress tone during sleep, so that we can pharmacologically augment genioglossus motor tone. Project 5 is a human study that uses our hypotheses about control of EEG arousal and the genioglossus muscle to generate and test a novel therapeutic approach to OSA. We hope that as we learn more about this brain circuitry in Projects 1-4, we will to refine our treatment methods in Project 5. Interactions among these Projects are also fostered by frequent meetings organized by Core A, including tri-weekly Investigator Meetings, attended by all Investigators, in which the Projects take turns presenting their progress and receiving feedback from colleagues to further improve their work; and by annual meetings of our Internal or External Advisory Boards, which provide input from outstanding scientists in this field that inform and refine our scientific approach. In addition, Projects 1-4 share many cutting edge optogenetic and patch clamp physiology methods that benefit from interactions with the Molecular Biology Core B and Electrophysiology Core C. The long term goal is to find a pharmacological approach through which at least a segment of the OSA population can reduce the frequency of apneas and subsequent EEG arousals, thus reducing the cognitive, metabolic, and cardiovascular consequences of OSA.